Overarching scientific challenge. The quest to model the genetic determinants of normal and diseased phenotypes has been at the core of biological research for the past century. However, genotype-phenotype relationships remain poorly understood. The central tenet of systems biology is that intricate networks of dynamic molecular interactions mediate genotype-phenotype relationships, while that of evolutionary biology is that genotype-phenotype relationships are governed by natural selection. I propose to establish an integrative research program aimed at deciphering how evolution shapes the organization of biological networks, in order to improve understanding of genotype-phenotype relationships. Current research goals. I aim to determine how the emergence of new genes contributes to the evolution of new traits and to the adaptation of species confronted with changing environments. I recently proposed that novel protein-coding genes can emerge de novo through transitory proto-genes generated by widespread translation of non-canonical transcripts (Carvunis et al., Nature 2012). This evolutionary model suggests a direct link between translational regulation and evolutionary adaptation. My current research aims at testing these predictions and investigating the dynamics and mechanisms underlying proto-gene evolution. Candidate and mentoring plan. With six first or co-first author publications in journals including Nature and Science, I have an impeccable track record of research productivity and creativity. Under the supervision of Prof. Vidal at Harvard Medical School, I have acquired superb training in all bioinformatics aspects involved in the annotation and evolutionary analysis of genomes and protein interaction networks. I have participated in large international collaborative projects, co authored review manuscripts and have had the pleasure to mentor many students. However, if I am to pursue my chosen research direction to its full potential, I need to develop a series of new skills in the next two years. I recently moved to the University of California in order to work wit an exceptional mentoring team. Together, Profs. Ideker (UCSD) and Weissman (UCSF) will i) teach me how to design and execute traditional and cutting-edge genomic experiments, ii) complement my computational training with integrative systems biology and next-generation sequencing bioinformatics skills, iii) help me plan and evaluate my own research, iv) train me in grant writing and laboratory management skills, and v) guide me during the transition to independence. I will also participate in formal training opportunities offered by the Office for Postdoctoral Scholar Affairs at UCSD and seek attendance at renowned Cold Spring Harbor Laboratory technical courses for intense experimental training. Proposed scientific plan for the mentored phase of the award. During the mentored phase of the award, I will investigate the translational regulation and adaptive potential of canonical protein-coding genes, which remain poorly understood. These research directions will improve modeling of cellular networks, gene expression and evolutionary adaptation, while allowing me to acquire new biological knowledge, establish experimental and computational pipelines, and acquire preliminary data, which I will subsequently exploit as an independent researcher. Proposed scientific plan for the independent phase of the award. With my strong background and the relevant training and data obtained during the mentored phase, I will be in a unique position to develop my original research as an independent investigator in one of the top American research institutions. I will have all the required expertise and maturity to successfully address the following questions. How large and how dynamic is the proto-gene reservoir? How do proto-genes influence fitness? Is the proto-gene model universal? This proto-gene research promises to reveal fundamental aspects of protein functions and to open exciting avenues of investigation in the fields of systems biology, genomics and evolution. I expect it will lay the foundation for subsequent grant applications and be the start of a productive independent research career. Determining whether the human genome contains proto-genes, as I strongly suspect, will be of great significance for public health.